Three animal tumor models have been established for the study of modulation of sensitivity to carcinogens. In the first, athymic nu/nu mice have been found to be sensitive to skin tumorigenesis by a variety of agents, including dimethylbenz[a]anthracene (DMBA), DMBA followed by repeated application of the promoter, TPA, and repeated application of methylnitrosourea (MNU). Distribution on the body, latency, and histology of the tumors differed with each of these treatments: a single dose of DMBA resulted mainly in sebaceous adenomas distant from the treatment site; DMBA followed by TPA yielded in addition papillomas at the site; and MNU caused rapidly-growing carcinomas at the site only. Five to ten times more tumors were found on the nu/nu compared to the nu/+ mice with all treatments. This system will be used to investigate physiological and cellular factors determining sensitivity to skin carcinogenesis. In the second model, the role of induction of aryl hydrocarbon metabolizing enzymes in susceptibility to systemic carcinogenesis by methylcholanthrene (MC) was investigated using six mouse strains of varying inducibility. Highly inducible strains (C57BL and BALB/c) experienced few deaths (10-20%) six to nine months after the start of oral dosing with MC, whereas 70-90% of noninducible mice (DBA and AKR) dies with tumor during this period. Strains of moderate inducibility (Swiss and C3H) exhibited an intermediate number of deaths (30-50%). Treatment of the mice with the enzyme inducer, betanaphthoflavone, prior to the MC resulted in reduced death rates for all strains. This project will be extended to other compounds, doses, and modes of administration, and may be useful in the design of practical cancer prevention measures for human populations. Thirdly, the high sensitivity of strain A mouse lung to rapid induction of tumors was used to confirm the carcinogenic action of a low dose (500 ppb in the water) of the environmental agent dimethylnitrosamine in mice fed different diets. This model will be further exploited to study modulation of dose-response and preneoplastic cellular changes during exposure to environmental levels of carcinogen.